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CDK4/6 Inhibitor Toxicity in HR+ Breast Cancer

Panelists: Joyce O Shaughnessy, MD, Baylor University Medical Center; Kevin Kalinsky, MD, MS NewYork-Presbyterian Hospital; Elizabeth Mittendorf Dana-Farber; Ruth O Regan, MD, University of Wisconsin Carbone Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Friday, Apr 05, 2019



Transcript: 

Joyce O’Shaughnessy, MD:
So let’s talk about the toxicity of the CDK4/6 [cyclin-dependent kinsases 4 and 6] inhibitors. I had a patient in the clinic this week who is responding with kind of luminal-B bone only, and she is sitting at an ANC [absolute neutrophil count] of 600. I had reduced her on palbociclib from the 125 mg to the 100 dose, but she still kind of sits around 600 or so. She’s doing very well on it—you know, asymptomatic. I’m probably going to leave her there, you know what I mean? What are you guys doing in that situation?

Kevin Kalinsky, MD, MS: I also tend to let it ride a bit. If you look at the package insert for these agents, if you have an ANC that’s less than 1000, you are supposed to dose reduce. If someone comes in at 800, 900, or if they’re doing well and they’re asymptomatic, I also just tend to let it go. I know some colleagues who also will go down to the 500s. I start to get nervous around that. It tends to be a laboratory value. Certainly, if they had infections, that’s a different story. But I also am not so strict about that specific cutoff. I don’t know if you guys have a similar approach?

Hope S. Rugo, MD: I generally do wait. I’m not sure exactly why, but I wait till they have an ANC of close to 1000 to restart the next cycle. But what I do is, if somebody takes 35 days to get there, then I have them start again at 35 days, as opposed to checking multiple blood counts in between. It doesn’t really make sense.

But we did present some data from a consortium trial from our TBCRC [Translational Breast Cancer Research Consortium] at San Antonio Breast [Cancer Symposium] where we looked at 100 versus 125 in people who had gotten chemotherapy before. It’s sort of something we don’t see a lot of anymore, but we did when we started that study. We looked at Rb [retinoblastoma protein] phosphorylation in keratinocytes in skin and found that there was equal inhibition of Rb phosphorylation and proliferating keratinocytes. It was kind of fascinating to suggest that if you did need to dose reduce, especially if they’re not on a trial, you could go down or you could go back up again. There are a lot of things you could do. In fact, 1 of my patients who has ITP [immune thrombocytopenia] takes 2 weeks on, 1 week off. So we tried all different things.

Joyce O’Shaughnessy, MD: That’s very interesting.

Ruth O'Regan, MD: Joyce, would you consider giving her abemaciclib instead?

Joyce O’Shaughnessy, MD: I’ve done that for 1 patient. She was really getting down there into grade 4 consistently, so I did switch her to abemaciclib. Fortunately, she kept responding, which was good. But at the grade 3 level for neutropenia, I’ve become more tolerant of it, I must say, you know?

I haven’t found a big difference. Interestingly, it’s enthusiastic to hear about the Rb phosphorylation. I haven’t seen a lot of difference in myelosuppression between the 125 and the 100 dose. If they’re otherwise feeling well and it’s just a paper toxicity, that’s kind of where I’ve been coming down. I haven’t had a lot of other toxicities besides myelosuppression from the palbociclib and the ribociclib. I haven’t seen QTc [QT interval corrected] prolongation.

Hope S. Rugo, MD: No. Liver function test abnormalities, sometimes. One of my patients on abemaciclib relapsed within a year of adjuvant AI [aromatase inhibitor] therapy and was on fulvestrant. Her primary toxicity was neutropenia. She never had a moment of diarrhea. And so, then you do really deal with the fact that you’re checking labs and the patient comes in and they’re neutropenic. So do you care? And generally, I didn’t. For her, she did totally fine on it. So now she unfortunately progressed after another year, in the liver. She has bad disease. But she was always a little neutropenic. So I didn’t change anything with the abemaciclib. But no diarrhea, which is so interesting, right? It’s just pharmacogenomics.

Joyce O’Shaughnessy, MD: That’s an interesting case, because she clearly had a luminal-B breast cancer, a very fast recurrence on AI, and had kind of moderate liver metastases?

Hope S. Rugo, MD: Well, she progressed in the bone when she developed new metastatic disease, but again needed surgery. And then she had great disease response for a year, but now is progressing in the liver. I think we see that in these patients who have very resistant disease.

Ruth O'Regan, MD: I think your patient, if they’re reliable, as long as they don’t have a fever, will probably be fine, right?

Joyce O’Shaughnessy, MD: Yes. You know, infection-wise, I just really haven’t seen anything.

Ruth O'Regan, MD: It begs the question of whether we overdo the labs. I never really understood why the day 15…. They’re not really going to make decisions on that.

Joyce O’Shaughnessy, MD: That’s right.

Ruth O'Regan, MD: And I know you were one of the first people to say that, Joyce.

Joyce O’Shaughnessy, MD: Yes.

Hope S. Rugo, MD: Do you check at day 15? I don’t check at day 15 on anybody. At the risk of being non–label-compliant, I never check.

Kevin Kalinsky, MD, MS: Yes, based on the label I tend to. But I think that’s right. Even if you look at abemaciclib, the median time to development of neutropenia is about 4 weeks. We’re checking every 2 weeks. It’s just, it doesn’t....

Ruth O'Regan, MD: It doesn’t make any sense.


Transcript Edited for Clarity

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Transcript: 

Joyce O’Shaughnessy, MD:
So let’s talk about the toxicity of the CDK4/6 [cyclin-dependent kinsases 4 and 6] inhibitors. I had a patient in the clinic this week who is responding with kind of luminal-B bone only, and she is sitting at an ANC [absolute neutrophil count] of 600. I had reduced her on palbociclib from the 125 mg to the 100 dose, but she still kind of sits around 600 or so. She’s doing very well on it—you know, asymptomatic. I’m probably going to leave her there, you know what I mean? What are you guys doing in that situation?

Kevin Kalinsky, MD, MS: I also tend to let it ride a bit. If you look at the package insert for these agents, if you have an ANC that’s less than 1000, you are supposed to dose reduce. If someone comes in at 800, 900, or if they’re doing well and they’re asymptomatic, I also just tend to let it go. I know some colleagues who also will go down to the 500s. I start to get nervous around that. It tends to be a laboratory value. Certainly, if they had infections, that’s a different story. But I also am not so strict about that specific cutoff. I don’t know if you guys have a similar approach?

Hope S. Rugo, MD: I generally do wait. I’m not sure exactly why, but I wait till they have an ANC of close to 1000 to restart the next cycle. But what I do is, if somebody takes 35 days to get there, then I have them start again at 35 days, as opposed to checking multiple blood counts in between. It doesn’t really make sense.

But we did present some data from a consortium trial from our TBCRC [Translational Breast Cancer Research Consortium] at San Antonio Breast [Cancer Symposium] where we looked at 100 versus 125 in people who had gotten chemotherapy before. It’s sort of something we don’t see a lot of anymore, but we did when we started that study. We looked at Rb [retinoblastoma protein] phosphorylation in keratinocytes in skin and found that there was equal inhibition of Rb phosphorylation and proliferating keratinocytes. It was kind of fascinating to suggest that if you did need to dose reduce, especially if they’re not on a trial, you could go down or you could go back up again. There are a lot of things you could do. In fact, 1 of my patients who has ITP [immune thrombocytopenia] takes 2 weeks on, 1 week off. So we tried all different things.

Joyce O’Shaughnessy, MD: That’s very interesting.

Ruth O'Regan, MD: Joyce, would you consider giving her abemaciclib instead?

Joyce O’Shaughnessy, MD: I’ve done that for 1 patient. She was really getting down there into grade 4 consistently, so I did switch her to abemaciclib. Fortunately, she kept responding, which was good. But at the grade 3 level for neutropenia, I’ve become more tolerant of it, I must say, you know?

I haven’t found a big difference. Interestingly, it’s enthusiastic to hear about the Rb phosphorylation. I haven’t seen a lot of difference in myelosuppression between the 125 and the 100 dose. If they’re otherwise feeling well and it’s just a paper toxicity, that’s kind of where I’ve been coming down. I haven’t had a lot of other toxicities besides myelosuppression from the palbociclib and the ribociclib. I haven’t seen QTc [QT interval corrected] prolongation.

Hope S. Rugo, MD: No. Liver function test abnormalities, sometimes. One of my patients on abemaciclib relapsed within a year of adjuvant AI [aromatase inhibitor] therapy and was on fulvestrant. Her primary toxicity was neutropenia. She never had a moment of diarrhea. And so, then you do really deal with the fact that you’re checking labs and the patient comes in and they’re neutropenic. So do you care? And generally, I didn’t. For her, she did totally fine on it. So now she unfortunately progressed after another year, in the liver. She has bad disease. But she was always a little neutropenic. So I didn’t change anything with the abemaciclib. But no diarrhea, which is so interesting, right? It’s just pharmacogenomics.

Joyce O’Shaughnessy, MD: That’s an interesting case, because she clearly had a luminal-B breast cancer, a very fast recurrence on AI, and had kind of moderate liver metastases?

Hope S. Rugo, MD: Well, she progressed in the bone when she developed new metastatic disease, but again needed surgery. And then she had great disease response for a year, but now is progressing in the liver. I think we see that in these patients who have very resistant disease.

Ruth O'Regan, MD: I think your patient, if they’re reliable, as long as they don’t have a fever, will probably be fine, right?

Joyce O’Shaughnessy, MD: Yes. You know, infection-wise, I just really haven’t seen anything.

Ruth O'Regan, MD: It begs the question of whether we overdo the labs. I never really understood why the day 15…. They’re not really going to make decisions on that.

Joyce O’Shaughnessy, MD: That’s right.

Ruth O'Regan, MD: And I know you were one of the first people to say that, Joyce.

Joyce O’Shaughnessy, MD: Yes.

Hope S. Rugo, MD: Do you check at day 15? I don’t check at day 15 on anybody. At the risk of being non–label-compliant, I never check.

Kevin Kalinsky, MD, MS: Yes, based on the label I tend to. But I think that’s right. Even if you look at abemaciclib, the median time to development of neutropenia is about 4 weeks. We’re checking every 2 weeks. It’s just, it doesn’t....

Ruth O'Regan, MD: It doesn’t make any sense.


Transcript Edited for Clarity
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